Radiation-responsive scintillating nanotheranostics for reduced hypoxic radioresistance under ROS/NO-mediated tumor microenvironment regulation

Theranostics. 2018 Nov 12;8(21):5870-5889. doi: 10.7150/thno.27351. eCollection 2018.

Abstract

Hypoxia-induced radioresistance is the primary reason for failure of tumor radiotherapy (RT). Changes within the irradiated tumor microenvironment (TME) including oxygen, reactive oxygen species (ROS) and nitric oxide (NO) are closely related to radioresistance. Therefore, there is an urgent need to develop new approaches for overcoming hypoxic radioresistance by incorporating TME regulation into current radiotherapeutic strategies.

Methods: Herein, we explored a radiation-responsive nanotheranostic system to enhance RT effects on hypoxic tumors by multi-way therapeutic effects. This system was developed by loading S-nitrosothiol groups (SNO, a NO donor) and indocyanine green (ICG, a photosensitizer) onto mesoporous silica shells of Eu3+-doped NaGdF4 scintillating nanocrystals (NSC).

Results: Under X-ray radiation, this system can increase the local dosage by high-Z elements, promote ROS generation by X-ray-induced photodynamic therapy, and produce high levels of NO to enhance tumor-killing effects and improve hypoxia via NO-induced vasodilation. In vitro and in vivo studies revealed that this combined strategy can greatly reinforce DNA damage and apoptosis of hypoxic tumor cells, while significantly suppressing tumor growth, improving tumor hypoxia and promoting p53 up-regulation and HIF1α down-regulation. In addition, this system showed pronounced tumor contrast performance in T1-weighted magnetic resonance imaging and computed tomography.

Conclusion: This work demonstrates the great potential of scintillating nanotheranostics for multimodal imaging-guided X-ray radiation-triggered tumor combined therapy to overcome radioresistance.

Keywords: X-ray induced photodynamic therapy; hypoxia-induced radioresistance; multimodal imaging; nanoscintillators; nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hypoxia / therapy*
  • Mammary Neoplasms, Animal / diagnostic imaging*
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / therapy*
  • Mice
  • Nanoparticles / administration & dosage*
  • Nanoparticles / radiation effects
  • Oxidants / administration & dosage*
  • Oxidants / metabolism
  • Photochemotherapy / methods*
  • Radiotherapy / methods*
  • Theranostic Nanomedicine / methods
  • Treatment Outcome
  • Tumor Microenvironment
  • X-Ray Therapy / methods
  • X-Rays

Substances

  • Oxidants